The invention relates generally to medical system and procedures and more particularly to devices and methods of their use for injection of a therapeutic agent into the surface of an interior body cavity of a living being.
Market expansion in cardiovascular and cardiothoracic surgery in past years has largely been driven by increases in open-heart surgical bypass procedures, but new opportunities for growth will come from products associated with least-invasive procedures. The positive outcomes seen thus far with these techniques, accompanied by continued physician acceptance, will lead to a gradual erosion of the market for traditional open-heart surgery.
Driven by capitation and cost-cutting measures associated with managed care, these evolving techniques and procedures not only hold the promise of reduced trauma to patients, but also reduce the significant costs associated with traditional open-heart surgery. Markets for least-invasive approaches to cardiothoracic surgery, including equipment and disposables, are predicted to grow at tremendous rates through the end of this century.
Within the past few years, an increasing number of centers worldwide have begun performing revolutionary techniques, such as beating-heart coronary artery bypass and laser transmyocardial revascularization (TMR). These developing procedures offer the potential of expanding the size of the eligible patient base by providing a viable alternative to patients unable to undergo open heart surgery, accelerated by significantly reduced patient trauma and, of course, the promise of lower costs.
Bone marrow cells and liquid aspirate are believed to be the source of angiogenic peptides known as growth factors. In addition, recent studies have shown that bone marrow cells include stem cells that differentiate into angioblasts. Angiogenesis represents the postnatal formation of new blood vessels by sprouting from existing capillaries or venules. During angiogenesis, endothelial cells are activated from a quiescent microvasculature (turnover of thousands of days) to undergo rapid proliferation (turnover of a few days).
In one technique currently in clinical stage testing employs transplantation of autologous bone marrow cells into the heart to restore heart function. Autologous bone marrow cells obtained by aspiration from the patient""s hip bone are transplanted into transventricular scar tissue for differentiation into cardiomyocytes to restore myocardial function (S. Tomita, et al., Circulation 100:19 Suppl II247-56, 1999. In another technique, autologous bone marrow cells are harvested and transplanted into an ischemic limb or cardiac tissue as a source of angiogenic growth factors, such as VEGF (A. Sasame, et al., Jpn Heart J, Mar 40:2 165-78, 1999).
Various types of bone marrow biopsy, aspiration and transplant needles and needle assemblies have been proposed and are currently being used. Many of them include a cannula, stylet with cutting tip, or trocar, that can be used to cut a bone marrow core sample. For withdrawal of liquid sample of bone marrow, an aspiration device comprising a hollow needle attached to a device for creating a negative pressure to aspirate the liquid bone marrow.
However, current procedures used for harvesting, purification and reinjection of autologous bone marrow cells require sedation of the patient for a period of three to four hours while the bone marrow aspirate is prepared for reinjection. In addition, the present procedure involves great risk of infection for the subject because the harvested bone marrow material is routinely aspirated in an operating or recovery room and then transferred after aspiration to a laboratory where the aspirate is placed into a centrifuge for gravity separation of bone marrow cells from the aspirate. In many cases the bone marrow aspirate is transferred into a specially designed centrifuge tube for the gravity separation. The separated bone marrow cells are then removed from the centrifuge tube into a syringe and delivered back to the recovery room or operating room for delivery to the patient. Generally, the processed cells are delivered to the body location where reperfusion is required by catheter. For example, delivery of bone marrow cells by pericardial catheter into the subject""s myocardium can be used to stimulate angiogenesis as a means of bypassing a blocked artery by collateral capillary development. However, prior art methods utilizing transfer of the material from the site of the aspiration for treatment at another site and/or into another vessel for separation risk introduction of pathogens with consequent increased risk of infection for the patient.
Angiogenic peptides like VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) have also entered clinical trials for treatment of coronary artery disease. Attempts are being made to devise clinically relevant means of delivery and to effect site-specific delivery of these peptides to ischemic tissue, such as heart muscle, in order to limit systemic side effects. Typically cDNA encoding the therapeutic peptide is either directly injected into the myocardium or introduced for delivery into a replication-deficient adenovirus carrying the cDNA to effect myocardial collateral development in a subject suffering progressive coronary occlusion. It is also known to transfect autologous bone marrow cells obtained as described above with such adenovirus for in vivo expression of the angiogenic peptide at the site of blockage. However, the handling of adenovirus vectors is generally considered a risk to the medical team members responsible for handling the vectors and/ or transfecting the bone marrow cells with the vectors. For this reason, current practice is to do such work xe2x80x9cunder the hoodxe2x80x9d to curtail possible escape of the adenovirus, thus requiring transport of the bone marrow to a laboratory setting for transfection and then return to the patient setting for reinjection of the transfected cells.
Moreover, the amount of extraneously introduced angiogenic growth factor, such as VEGF, that can be tolerated by the subject is very small. At high doses VEGF is known to cause a drop in blood pressure. Over dosage has proven to be fatal in at least one clinical trial. Thus strict control of the amount of growth factor delivered is of great importance. In addition, since the delivery site is located along the surface of an interior body cavity, such as the pericardium, a deflectable intravascular catheter with an infusion needle is customarily used, but it is difficult to tell whether the needle penetrates substantially orthogonally to the tissue surface so that the therapeutic is delivered at a single location or at an angle so that the therapeutic is delivered across a greater area. Thus, it is difficult to control the amount of therapeutic introduced at a single location.
In addition, controlling the depth of needle penetration is complicated by the tendency of prior art deflectable infusion catheters to withdraw the needle into the catheter when the catheter is deflected to approach the wall of an internal organ, thereby increasing the effective length of the catheter. In compensation for needle withdrawal, it is current practice to advance the needle from the tip of the catheter an extra distance to allow for withdrawal of the needle back into the catheter as the catheter is deflected. As a result, it is difficult to control the exact depth of needle penetration. In some cases, where the catheter is advanced into the pericardial space to deliver a therapeutic fluid into the myocardium, the needle has actually punctured the wall of the heart due to over-penetration, with the result that the therapeutic fluid is not introduced into the myocardium at all.
Many other therapeutic substances are also introduced into the surface of interior body cavities. For example, the reverse of angiogenesis is practiced for a number of therapeutic purposes, such as the prevention of restenosis following a reperfusion procedure or in treatment of diabetic retinopathy and cancer. In anti-restenosis, the growth of new blood vessels is blocked or curbed and the formation of new tissue (e.g., a growing tumor, neointima on the surface of a stent or vascular prosthesis, etc.) is limited or eliminated by introduction of xe2x80x9creverse angiogenesisxe2x80x9d agents, such as angiostatin, endostatin or, antarin, a locally administered mitotoxin that inhibits cell proliferation into the tissue.
Various types of tissue injection catheters have been developed to address the problem of injecting angiogenic agents into the interior of a body cavity, such as blood vessels or the myocardium of the heart. For example, U.S. Pat. No. 6,217,554 discloses a catheter designed to deliver therapeutic substances extravascularly. Once advanced through the vasculature, an advancement mechanism on the catheter is actuated to advance a plurality of hollow needles positioned on a slideably mounted tubular member, wherein the needles are biased to curve outwardly to penetrate the vasculature and deliver the therapeutic substance extravascularly. Another type of drug injection catheter disclosed in PCT application US99/22679 (WO 01/24852) discloses a needle slideably mounted on tubing contained within the catheter and utilizes a tracking system of transducers in the distal end of the catheter as well as transducers external to the patient to target angiogenic drugs to ischemic tissue. Yet another type of drug delivery catheter disclosed in PCT application US00/28301 and U.S. Pat. No. 5,782,824 includes a distal helical coil that can be operated from the proximal end of the catheter to engage and penetrate the myocardium.
Despite these advancements in the art, there is a need in the art for new and better equipment for use in handling and treating autologous bone marrow and for controlled delivery of fluid containing cells, nucleic acid encoding therapeutic peptides, and the like, into interior body cavities, especially into the vasculature and the interior or exterior of the heart to induce or curtail angiogenesis. In particular, there is a need in the art for an injection catheter with an injection needle that penetrates a controlled distance into tissue, for example, into the wall of a body cavity. In addition, there is need for new and better catheters adapted to inject a controlled amount of a therapeutic substance to a defined area of an interior body cavity or to aspirate fluids from an interior body cavity. The present invention satisfies these needs and provides additional advantages.
The invention overcomes many of the problems in the art by providing methods for injecting a therapeutic fluid a controlled distance into the surface of an interior body cavity in a subject in need thereof. In one embodiment, the invention methods for controlled depth injection comprise
(a) introducing a catheter into the interior of a body cavity by advancing the catheter through the vascular system of the subject, said catheter comprising:
i) an elongate hollow catheter body having a proximal end and a distal end with a flexible portion at the distal tip thereof, said catheter body being sized and constructed to be advanced intravascularly into an interior body cavity of a subject;
ii) a hollow needle housed throughout the catheter body, said needle having a distal portion with a sharp tip and a proximal portion in fluid communication with a fluid source, said needle further having a retracted needle position wherein the sharp tip of the needle is disposed within the catheter body, and an advanced needle position wherein the sharp tip of the needle extends a fixed distance beyond a distal end face of the catheter body,
iii) a needle stop attached to the needle that tethers the distal portion of needle during flexure while the proximal portion of the needle remains freely slideable within the catheter body, and
iv) an advancement mechanism attached to the needle for advancing the needle distally a fixed distance to the advanced needle position;
wherein the needle stop prevents withdrawal of the distal portion of the needle into the catheter body upon flexure of the catheter prior to actuation of the advancement mechanism to advance the needle to the advanced needle position, thereby exposing a fixed length of the sharp tip of the needle;
(b) contacting the surface of the body cavity with the distal portion of the catheter,
(c) advancing the sharp distal portion of the injector needle the controlled distance into the surface of the body cavity; and
(d) introducing a therapeutic amount of a therapeutic fluid into the surface of the body cavity through the sharp tip of the injector needle.
In another embodiment, the present invention provides methods for promoting angiogenesis of an area of a heart by introducing an invention catheter into the interior of the heart through the vascular system of the subject; contacting the myocardium of the heart with the distal portion of the catheter; advancing the sharp distal portion of the injector needle the controlled distance into the myocardium; and introducing a therapeutic amount of an angiogenesis-promoting fluid a precisely controlled depth into the myocardium at multiple spaced locations through the sharp tip of the injector needle.
In another embodiment, the present invention provides methods for promoting angiogenesis of an area of a heart by introducing a hollow needle a precisely controlled distance into the epicardium of the heart of the subject during a surgical procedure, and injecting an angiogenesis promoting fluid comprising autologous bone marrow aspirate of the subject in a substantially sterile condition into the epicardium via the hollow needle at a plurality of spaced locations; wherein therapeutic fluid is introduced at a controlled depth in the range from about 0.1 cm to about 2 cm and wherein the volume of the fluid introduced at each of the locations is controlled to be in the range from about 0.1 ml to about 3.0 ml.